The prevalence of foot onychomycosis in regions with different climatic conditions varies from 4 to 21%. The use of modern antifungal medications does not provide a high curing rate for foot onychomycosis with unfavorable prognostic factors. Therapy of patients from risk groups of the development of adverse events upon using systemic antimycotic agents, such as terbinafin and itraconazole, is of particular challenge. The aim of the study was to demonstrate the advantage of combined therapy for foot onychomycosis (fluconazole and amorolfin) over monotherapy (fluconazole) in patients with foot onychomycosis with prognostically unfavorable clinical manifestations. Material and methods. According to its design, the trial was single center, open, prospective, randomized, and comparative. After screening, 300 patients suffering from foot onychomycosis with prognostically unfavorable clinical manifestations were included into the trial. The patients were divided into two groups of 150 people each: the 1st group received combined therapy with fluconazole (Diflucan) and amorolfin nail varnish (Loceril); the 2nd group was subjected to fluconazole monotherapy (Diflucan). Results. The study of patients with foot onychomycosis demonstrated that the complete efficacy of combined anitungal therapy was 59.1%, while the complete efficacy of monotherapy with systemic antimycotic was lower by 15.2% and amounted to 43.9% (χ2df=1; p<0.001). Conclusion. Thus, the therapy combining fluconazole and amorolfin nail varnish in patients with foot onychomycosis with prognostically unfavorable clinical manifestations is more effective than fluconazole monotherapy. The high level of fluconazole safety enables its administration to foot onychomycosis patients with a high risk of adverse events.